This application is a U.S. national stage application of PCT/CN2014/073483, having an international filing date of Mar. 14, 2014, which claims priority to PCT/CN2013/072771, having an international filing date of Mar. 15, 2013, each of which the entire contents are incorporated herein by reference.
Incorporated herein by reference is the Sequence Listing being submitted via EFS-Web as an ASCII text file named 13606-001-999_Sequence_Listing.TXT, created Jan. 23, 2015, and being 36,711 bytes in size.
The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 7, 2016, is named 13606-001-999_SL.txt and is 40,868 bytes in size.
Diabetes mellitus (DM) afflicts over 300 million people worldwide. There are two main types of DM: type 1 DM (T1D) and type 2 DM (T2D). T1D results from the body's failure to produce insulin, and requires the patient to administer insulin daily. T2D results from insulin resistance, a condition in which cells fail to use insulin properly. There are many approved non-insulin therapies for T2D. However, there is a large portion of late stage T2D patients requiring insulin administration due to the loss of β-cell function as the disease progresses.
Development of diabetes is associated with substantial losses in pancreatic islet mass. At the time of diagnosis, over 90% of islet mass has been lost in T1D patients, and approximately 50% has been lost in T2D patients. Many attempts have been made in quest of a potential stimulus for islet neogenesis, which is considered as the optimal treatment for both T1D and T2D.
Recently, investigators have shown that islet neogenesis-associated protein (INGAP) from hamster, human proIslet peptide (HIP), glucagon like peptide-1 (GLP-1), islet endocrine neuropeptide vasoactive intestinal peptide (VIP), epidermal growth factor and gastrin, and others, are capable of inducing pancreatic progenitor cells, located in the nonendocrine fraction of the pancreas, to differentiate into fully functional islets in various animal models. Among these compounds, INGAP peptide (INGAP-PP), a 15-mer peptide derived from the sequence of INGAP at amino acids 104-118, has been shown to induce islet neogenesis in multiple animal models, reverse streptozotocin (STZ) induced diabetes in mice, increase C-peptide secretion in T1D patients, and improve glycemic control in T2D patients. Additional biological effects of INGAP-PP have been reported, including dose dependent stimulation of expansion of β-cell mass, β-cell replication, reduced β-cell apoptosis, and increased insulin secretion. In human studies, there was an effect with an improvement of glucose homeostasis, confirmed by HbA1c reduction at 90 days in patients with T2D, and by a significant increase in C-peptide secretion in patients with T1D. However, the short plasma half-life of INGAP-PP and the need for administration in a high dose have significantly limited clinical applications of this peptide.
HIP, the bioactive peptide encoded by a portion of the human regenerating islet-derived 3 alpha (REG3A) gene, is the human homolog of the INGAP peptide. Previous studies have shown that treatment of human pancreatic ductal tissues with HIP stimulated the production of insulin. Administration of HIP improved glycemic control and increased islet number in diabetic mice. The stabilized form of HIP has been tested in a single ascending dose clinical trial with the goal of exploring the tolerability, safety and pharmacokinetics. Like INGAP-PP, high dose is required of HIP, thus significantly limit clinical applications of the parent HIP peptide.
Thus, there exists a need to develop additional drugs for treatment of diabetes or other diseases associated with impaired pancreatic function. The present invention addresses this need, and provides related advantages as well.